tbuckley/cabot-search huggingface dataset:
Abstract 582: IDO1 inhibition sensitizes metastatic lung tumors to hypoxia/ER stress targeting agent-induced cell death
Authors: Shih-Chun Shen, Souvik Dey, James B. DuHadaway, George C. Prendergast, Alexander J. Muller
Journal: Cancer Research (2023)

Abstract IDO1 (indoleamine 2,3-dioxygenase), a tryptophan catabolic enzyme, has been demonstrated in our previous studies to support neovascularization by counteracting IFNγ-mediated anti-angiogenesis through IDO1-induced IL6. Physiologically, we observed that the reduced neovascularization associated with IDO1 loss was accompanied by increased intra-tumoral hypoxia within lung metastases of 4T1 breast tumors while eliciting little tumor cell death, lessening the prospects for direct clinical benefit. Several agents have been developed to be selectively cytotoxic under hypoxic/nutrient-deprived conditions, suggesting the potential for therapeutic cooperativity. Inhibiting PERK, a UPR (unfolded protein response) activator, has been shown to promote tumor cell apoptosis under hypoxic conditions both in vitro and in vivo. In Ido1-/- 4T1 tumor-bearing mice, administration of the PERK inhibitor GSK2656157 elicited pronounced metastatic tumor cell death that was elevated significantly over WT controls. Similarly, when WT 4T1 tumor-bearing mice were administered GSK2656157 together with the IDO1 inhibitors Epacadostat, Indoximod or Navoximod, the attenuated neovascularization and elevated regional hypoxia in lung metastases elicited by IDO1 inhibition was accompanied by an increased level of tumor cell death. Co-administration of the hypoxia-activated prodrug Evofosfamide with Epacadostat likewise resulted in elevated metastatic tumor cell death. This contrasts with results obtained with the non-targeted cytotoxic agent Carboplatin that elicited comparable levels of metastatic tumor cell death regardless of Epacadostat co-administration. Altogether, these data establish the potential to benefit treatment in tumor settings where IDO1 inhibition enhances intra-tumoral hypoxia through neovascular regression by facilitating the ability of hypoxia-targeting agents to effectively eliminate tumor cells in a more targeted manner than can be achieved with conventional chemotherapy. Citation Format: Shih-Chun Shen, Souvik Dey, James B. DuHadaway, George C. Prendergast, Alexander J. Muller. IDO1 inhibition sensitizes metastatic lung tumors to hypoxia/ER stress targeting agent-induced cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 582.
Abstract 6233: Omacetaxine reduces c-MYC expression and demonstrates antitumor effects in osteosarcoma
Authors: Kristen B. Farrell, Douglas H. Thamm
Journal: Cancer Research (2023)

Abstract Omacetaxine mepesuccinate (OMX), also known as homoharringtonine, is a protein translation inhibitor approved for use in chronic myeloid leukemia. Recent studies suggest OMX may be effective against other cancer types with high rates of protein translation, and may be successful against protein targets that are difficult to inhibit by reducing their translation rates. Using both canine and human osteosarcoma (OS) cell lines, we have investigated the efficacy of OMX against osteosarcoma and expression of c-MYC. OMX provides significant growth inhibition of OS cells with IC50 values in the low nanomolar range. OMX also reduces migration and invasion capabilities of OS cells. Strikingly, we observed reduction in levels of c-MYC protein in most canine and human OS cell lines after OMX exposure. This reduction was both dose and time dependent. We also investigated the efficacy of OMX against OS in an orthotopic mouse OS model. OMX is a promising candidate for treatment of OS in both dogs and humans, and potentially additional cancers dependent on c-MYC. Citation Format: Kristen B. Farrell, Douglas H. Thamm. Omacetaxine reduces c-MYC expression and demonstrates antitumor effects in osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6233.
Abstract 4951: Proteasome inhibitor carfilzomib induces apoptosis via downregulation of AKT pathway in HPV negative HNSCC
Authors: Woo-Jin Jeong, Jiyeong Kim, Hye-Yeon Lee, Zhiyong Wang, Walt Amornphimoltham, Silvio Gutkind
Journal: Cancer Research (2023)

Abstract Background Head and neck squamous cell carcinoma (HNSCC) presents in heterogenous sites, varied etiology and risk factors, and has diverse genetic background which confer dissimilar response to treatments, including chemotherapy. Here we tested the hypothesis that investigation of HPV presence in a HNSCC cell line would identify pathway contributing to oncogenesis of other HNSCC. We sought to identify pathways that differentially affect HNSCC according to the genetic background, therefore identifying targets and suitable candidate for treatment. We used genetic and pharmacological approaches to inhibit AKT pathway in HNSCC cell lines. Materials &amp; methods Chemical genetic library screening against 6 HNSCC cell lines were performed. The high throughput combinatorial small molecule screening for cell viability and apoptosis was carried out. Candidate agents were validated in both CAL-27 (HPV-negative) and UM-SCC-47 (HPV-positive) cell lines. Identified pathways and representative targeted agents were validated in vitro. Expression of related protein were confirmed by western blot assay. Results EGFR, PIK3CA, mTOR, CDK1, HSP90AB1, HDAC1, and PSMD1 pathways were identified to be susceptible pathways in HNSCC using high throughput chemical genetic library screening. In vitro validation of carfilzomib showed IC50 of 7.07nM in CAL-27 cells and IC50 of 26.3nM in UM-SCC-47 cells. Knockdown of PSMD1 transcripts by transfected siRNAs reduced CAL-27 cells viability. Carfilzomib regulates the AKT pathway by decreasing t-AKT, p-AKT, p-ERK, p-S6 proteins and increasing p21 in CAL-27. Conclusion Inhibition of AKT pathway treatment with proteasome inhibitor carfilzomib is effective in HPV-negative HNSCC cells. Taken together, our findings reveal carfilzomib induced the apoptotic pathway and suggest that carfilzomib, the representative of a new class of chemotherapeutic drug, may be utilized for overcoming cisplatin-resistance in human SCC. Citation Format: Woo-Jin Jeong, Jiyeong Kim, Hye-Yeon Lee, Zhiyong Wang, Walt Amornphimoltham, Silvio Gutkind. Proteasome inhibitor carfilzomib induces apoptosis via downregulation of AKT pathway in HPV negative HNSCC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4951.
Abstract 5795: Leukemic stem cells confer ferroptosis resistance in aggressive blood cancer
Authors: Nunki Hassan, Hangyu Yi, Lucie Gaspard-Boulinc, Jenny Wang
Journal: Cancer Research (2023)

Abstract Acute myeloid leukemia (AML) is an aggressive blood cancer with limited therapeutic options against leukemic stem cells (LSCs), resulting in poor clinical outcomes for decades. We have demonstrated the clinical importance of aberrant activation of RSPO3/β-catenin pathway in a subset of poor prognosis AML (Cancer Cell, 38:263-278, 2020) and its ability to sustain low levels of reactive oxygen species (ROS), a critical characteristic of human LSCs. This current study has extended our recent finding, and for the first time linked the pathway activation to ferroptosis resistance, a new drug resistance mechanism in cancer therapy. Our single-cell multiomics data in patient-derived xenograft mouse models of relapsed AML showed that the pathway activation in human LSCs led to upregulation of 43 differentially expressed genes associated with iron detoxification (e.g., FTH1) and ROS sensing/detoxification (e.g., PRDX1), two key features of ferroptosis resistance. Consistent with this observation, we found that AML patient specimens with favourable outcomes, which are independent of RSPO3 pathway, were sensitive to RSL3 treatment leading to increased cell death associated with elevated levels of intracellular ROS and iron. In contrast, AML patient specimens with poor clinical outcomes, which critically depend on RSPO3 pathway activation for survival and maintenance of myeloid undifferentiated state, revealed resistance to ferroptosis inducers (e.g., RSL3). Intriguingly, we found that anti-RSPO3 antibody, a clinical-grade drug that inhibits AML LSCs by blocking the interaction of RSPO3 with its receptor, sensitizes human LSCs to RSL3 treatment, leading to reduced cell viability. Overall, this study is the first to demonstrate the role of ferroptosis resistance in human LSCs and provides an opportunity to develop precision combination therapy by concurrently targeting self-renewal and ferroptosis resistance to improve therapeutic outcomes for patients with poor-risk AML. Citation Format: Nunki Hassan, Hangyu Yi, Lucie Gaspard-Boulinc, Jenny Wang. Leukemic stem cells confer ferroptosis resistance in aggressive blood cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5795.
Abstract 6235: Discovery of novel HDAC6 inhibitors that enhance proteasomal activity to boost antigen presentation and trigger anti-myeloma T-cell immunity
Authors: Priyanka S. Rana, James Ignatz-Hoover, James J. Driscoll
Journal: Cancer Research (2023)

Abstract Transformative success of cancer immunotherapy has revolutionized cancer treatment and can induce long lasting responses in patients with cancers from a wide range of histologies. However, only a fraction of patients respond to immunotherapy and cancer cells escape immunosurveillance through molecular mechanisms that remain elusive. Proteasomes play a central role in the immune response by generating peptides from intracellular antigens which are presented on the cell surface for recognition by CD8+ cytotoxic T lymphocytes (CTLs). Malignant cells employ strategies to downregulate antigen presentation and impair CTL-mediated tumor recognition and lysis. Recently, we discovered that HDAC6-specific inhibitors increased intracellular proteasome activity and the generation of antigenic class I MHC peptides. However, current HDAC6 inhibitors have pharmacologic liabilities that limit efficacy, e.g., low potency and solubility, poor pharmacokinetic properties and potential genotoxicity. Therefore, we performed a cell-based, high-throughput screen (HTS) of 9,600 HDAC-specific compounds to identify novel compounds that increased proteasomal activity in myeloma cells. We identified 8 hits that increased proteasomal activity at least two-fold. Importantly, two novel molecules identified in the HTS increased proteasome activity more potently and more rapidly than the HDAC6-specific inhibitors Tubastatin-A and ACY-1215 (Ricolinostat) with comparatively low cytotoxicity. Proteasomes degrade chicken ovalbumin (Ova) to generate the immunodominant antigen SIINFEKL presented at the cell surface complexed with the MHC-class I molecule H-2Kb. Treatment of tumor cells with Tubastatin-A and ACY-1215 increased levels of the MHC-class I-SIINFEKL complex by ~3-fold. Tumor cells were pretreated with Tubastatin-A and ACY-1215 and then co-cultured with CTLs that had been genetically-engineered to express a SIINFEKL-restricted T-cell receptor (TCR). Pre-treatment of lymphoma or multiple myeloma cells with novel HDAC6 inhibitors also increased tumor lysis by CTLs that expressed the SIINFEKL-restricted TCR by 2-fold. Taken together, our results support repositioning pharmacologics that inhibit HDAC6 to activate proteasomal generation of antigenic peptides and boost antigen presentation as cancer immunotherapeutics. Citation Format: Priyanka S. Rana, James Ignatz-Hoover, James J. Driscoll. Discovery of novel HDAC6 inhibitors that enhance proteasomal activity to boost antigen presentation and trigger anti-myeloma T-cell immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6235.
Abstract 5808: Integrin-linked kinase regulates Wnt transcriptional activity in platinum resistant ovarian cancer stem cells
Authors: Rula Atwani, Virginie Lazar, George Earl Sandusky, Salvatore Condello
Journal: Cancer Research (2023)

Abstract Ovarian cancer (OC) is the most lethal gynecological cancer, characterized by chemo-resistance and fatal tumor recurrence after primary treatment. The metastatic progression is mediated by exfoliation of tumor cells into the peritoneal cavity, the formation of compact OC spheroids, and their implantation onto the overlying peritoneal surface. Spheroid formation is promoted by a change of cell adhesion properties, enhanced secretion of extracellular matrix (ECM) components, such as fibronectin (FN), that stiffen the tumor stroma, promote the aberrant activation of integrins, and recruit the adaptor protein integrin-linked kinase (ILK). ILK drives cytoskeletal assembly and modulates key processes, including survival, invasion, and stemness. However, the functional role of ILK in chemoresistance of ovarian cancer stem cells (OCSCs) remains incompletely understood. We tested the hypothesis that the formation of FN-integrin complexes at the cell membrane promotes survival of OCSCs and supports OC spheroid formation by activating ILK and downstream oncogenic signaling. In OCSCs compared with non-CSC, ILK, FN, and integrin β1 mRNA expression levels were increased (P&amp;lt;0.001) and further enriched in OC spheroids compared with monolayers (P&amp;lt;0.01). ILK blockade with the specific inhibitor cpd-22 suppressed spheroid proliferation and tumor initiating capacity in xenograft mouse model. Furthermore, key oncogenic signaling pathways, in particular decreased β-catenin signaling essential to sustaining cancer cell stemness, were altered in OC spheroids treated with cpd-22. Of the genes examined, expression of Wnt receptor Frizzled 7 (Fzd7) was the mostly highly downregulated in OC spheroids treated with cpd-22, indicating a direct correlation between ILK activation and Wnt signaling. By using co-immunoprecipitation and proximity ligation assay, we demonstrated that ILK co-localizes with Fzd7 in OC spheroids. Mechanistically, treatment of OC spheroids with the combination of carboplatin and ILK-Fzd7 blockade decreased β-catenin signaling, inhibited phospho-Akt at Ser473 and increased levels of cleaved-caspase-3 compared to single agent alone, resulting in apoptosis. By regulating β-catenin signaling, Fzd7 expression and ILK activation are essential for OCSCs survival. Targeting Fzd7-ILK clusters may represent a new therapeutic approach to eradicate OCSC and ultimately improve patient outcomes. Citation Format: Rula Atwani, Virginie Lazar, George Earl Sandusky, Salvatore Condello. Integrin-linked kinase regulates Wnt transcriptional activity in platinum resistant ovarian cancer stem cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5808.
Abstract 4959: TIC10/ONC201 activates ClpP to degrade ALAS1 while PG3 does not degrade ALAS1 in pathway to HRI, ATF4 and CHOP activation leading to tumor cell death
Authors: Xiaobing Tian, Wafik S. El-Deiry
Journal: Cancer Research (2023)

Abstract TRAIL-inducing compound TIC10/ONC201 binds and activates mitochondrial protease ClpP leading to integrated stress response (ISR) and ATF4 transcription factor activation. Our lab previously reported that ONC201 activates HRI (heme-regulated inhibitor) kinase but does not signal eIF2-alpha phosphorylation through PERK or GCN2. However, the connection between ClpP activation of HRI remains unknown. PG3, a prodigiosin analog that bypasses a defective p53 pathway potently induces ATF4 and pro-apoptotic PUMA. Our data indicate that PG3 activates ATF4 through ISR via HRI as knockdown of HRI but not PKR blocked upregulation of ATF4 and CHOP in several tumor cell lines. We have been exploring how ClpP activation leads to HRI and ISR activation, and the mechanism by which PG3 leads to HRI activation. We find that activation of HRI by PG3 or ONC201 is not through the OMA1/DELE1◊HRI activation pathway. Moreover, ROS and NO are not responsible for ONC201- or PG3-induced HRI activation. ALAS1 (5'-aminolevulinate synthase 1) catalyzes the first rate-limiting step in heme (Iron-protoporphyrin) biosynthesis. ONC201 treatment leads to potent downregulation and inhibition of ALAS1, indicating that ONC201 inhibits heme biosynthesis. It is well known that reduced heme results in activation of the HRI kinase. We show that an inhibitor of heme biosynthesis or knockdown of ALAS1 results in HRI activation, while knockdown of HRI blocks upregulation of ATF4 by ONC201. Knockdown of ClpP rescues ONC201-induced downregulation of ALAS1 which blocks ONC201-induced upregulation of CHOP. Our studies identify a novel link between ClpP activation induced by ONC201 treatment and ATF4 upregulation, via the ClpP/ALAS1◊HRI◊ATF4/CHOP pathway. However, PG3 does not inhibit ALAS1, reduce its expression or therefore signal through ClpP. PG3 treatment did not lead to degradation of ALAS1, indicating that PG3 does not activate ClpP as ALAS1 is a known ClpP direct substrate. We are further investigating the signaling pathway that leads to PG3-induced activation of HRI. Our results suggest that different small molecule inducers of the ISR such as ONC201 and PG3 can achieve an anti-tumor effect through different pathways involving kinase HRI ultimately leading to ATF4/CHOP activation and tumor cell death. Citation Format: Xiaobing Tian, Wafik S. El-Deiry. TIC10/ONC201 activates ClpP to degrade ALAS1 while PG3 does not degrade ALAS1 in pathway to HRI, ATF4 and CHOP activation leading to tumor cell death. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4959.
Abstract 5801: Inhibition of muscarinic acetylcholine receptors in glioma stem cells blocks tumor progression
Authors: Sumyuktha V. Anand, Min K. Lee, Alexander G. Skorput, Isabella B. Fox, Alison L. Young, Brock C. Christensen, Allan Gulledge, Matthew C. Havrda
Journal: Cancer Research (2023)

Abstract Primary gliomas arising within the brain are the deadliest form of brain cancer and account for 78% of all malignant brain tumors. Glioma patients have a 5 percent five-year survival rate and drug-resistant tumors often recur following surgical resection and treatment with radiation and/or chemotherapy. The cancer stem cell hypothesis suggests the presence of a subset of undifferentiated cells, namely glioma stem cells (GSCs), in the heterogenous tumor mass responsible for disease progression. Understanding mechanisms responsible for maintaining GSCs and developing strategies to deplete the GSC population could improve glioma treatment and prognosis. Some GSCs are similar to oligodendrocyte precursor cells (OPCs), which are observed in neural development and the adult brain. OPCs are prone to malignant transformation and are believed to be a cell of origin for glioma. Recent findings indicate that the well-characterized neurotransmitter acetylcholine (ACh) maintains the primitive state of normal OPCs via muscarinic ACh receptors (mAChRs) preventing maturation and cell cycle exit. We hypothesized that cholinergic signaling may also maintain the primitive state of OPC-like GSCs. We analyzed publicly available single nuclei RNASeq data of patient glioblastoma samples and observed high expression of CHRM3, encoding the M3 mAChR, in OPC-like cells of the proneural subtype of glioma. Studies in mouse OPC-like GSCs confirmed high levels of CHRM3 expression and demonstrated that ACh generated voltage changes and rapid (&amp;lt; 1 second) increases in cytosolic calcium from internal calcium stores. Exposure to a brain permeant FDA-approved anti-muscarinic drug targeting M3mAChR suppressed proliferation, evoked calcium release, and the activation of intracellular second messengers PKC and ERK. Pharmacologic inhibition of mAChRs in established patient derived glioma grafts prevented re-initiation of tumors in subsequent host animals compared with vehicle treated tumors. These studies suggest that the cholinergic microenvironment maintains GSCs in a manner similar to normal OPCs and provides a platform for repositioning available small molecule mAChR antagonists for treatment of glioma. Citation Format: Sumyuktha V. Anand, Min K. Lee, Alexander G. Skorput, Isabella B. Fox, Alison L. Young, Brock C. Christensen, Allan Gulledge, Matthew C. Havrda. Inhibition of muscarinic acetylcholine receptors in glioma stem cells blocks tumor progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5801.
Abstract 5821: Synergism of FAK and ROS1 inhibitors in the treatment of <i>CDH1</i>-deficient cancers mediated by FAK-YAP-TRX signaling
Authors: Jiaming Gao, Yunying Yao, Zaiqi Wang, Baoyuan Zhang, Ruibao Ren
Journal: Cancer Research (2023)

Abstract CDH1 deficiency is common in triple negative breast cancer and diffuse gastric cancer patients, both of which lack effective therapeutics. Although inhibiting ROS1 function results in synthetic lethality in CDH1-deficient cancers, adaptive resistance limits their potential clinical benefits. Hyperactive focal adhesion kinase (FAK) signaling contributes to adaptive drug resistance, and FAK inhibitors are partially effective against CDH1–deficient cancers. Thus, co-treatment with ROS1 and FAK inhibitors may provide stronger anti-cancer effects by targeting CDH1 deficiency and potentially overcome drug resistance. Here, we evaluated the effects and mechanisms of combined treatment with FAK inhibitor IN10018 and ROS1 inhibitors. Cell-based assays and in vivo animal experiments revealed that FAK and ROS1 inhibitor combination treatment showed stronger anti-cancer effects than either monotherapy. ROS1 inhibitors induced FAK-YAP-TRX signaling, decreasing oxidative stress–related DNA damage, and consequently reducing its anti-cancer effects. However, the combination treatment suppressed the aberrant FAK-YAP-TRX signaling, reinforcing the cytotoxicity of ROS1 inhibitor towards cancer cells. This mechanism of action was confirmed by inhibiting the activity of FAK-YAP-TRX downstream signaling molecules and by pretreatment with oxidative stress scavengers. These findings support the co-administration of FAK and ROS1 inhibitors as a therapeutic strategy in CDH1-deficient triple negative breast cancer and diffuse gastric cancer patients and support further clinical testing of this combination regimen. Citation Format: Jiaming Gao, Yunying Yao, Zaiqi Wang, Baoyuan Zhang, Ruibao Ren. Synergism of FAK and ROS1 inhibitors in the treatment of CDH1-deficient cancers mediated by FAK-YAP-TRX signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5821.